Precision coordination of therapeutic and prophylactic antibiotics to reduce infection, toxicity, and emergence of resistance following acute abdominal surgery

急性阑尾炎是世界上最常见的腹部外科急症，一生的风险为8.6% 男性为6.9%，女性为6.9%。在美国，急性阑尾炎影响28万人，并导致1 每年住院天数为100万天。阑尾切除术后手术部位感染的发生率 不复杂、未穿孔的阑尾炎仍然高得令人无法接受。最近的一篇综述报告了盆腔脓肿 阑尾切除术后发生率为9.4%。腹膜微生物污染的风险最高的是 当阑尾被横切时。无论手术方法如何，保留的阑尾残端总是 将阑尾粘膜和腔细菌暴露在通常无菌的腹膜腔内。因此，至关重要的是 最佳的抗生素组织暴露发生在手术风险窗口期间。 急性阑尾炎的抗生素干预是复杂的。治疗性抗生素是从经验上开始的 急诊科，通常在阑尾切除前几个小时(通常需要等待4-18个小时)。因此，在 手术时，船上已经有治疗性抗生素，预防性抗生素的作用尚不清楚。 到目前为止，关于治疗性和预防性抗生素的混合使用还没有达成共识。 手术，在许多情况下，不进行预防，因为治疗性抗生素已经 已经被注射了。不幸的是，在这些情况下，抗生素组织水平可能低于最低限度 阑尾横切时的抑制浓度，因其半衰期较短且缺乏协议 与手术切开相关的给药时机。因此，附录，一个已知的微生物群库， 在阑尾切除过程中，结肠的管腔向腹膜开放，以保证一定水平的组织和 手术过程中腹膜微生物污染，增加SSI和脓肿形成的风险。A更多 急性阑尾炎患者个体化给药方法可降低SSI风险 不必要的抗生素使用，减少过量使用的风险，并遏制抗生素耐药性的发展。 我们假设，基于手术时间的个性化抗生素剂量可以 优化手术部位的组织抗生素暴露，避免使用不必要的抗生素(选择性 抗生素抗药性压力)，并降低毒性。因此，我们的具体目标是1)描述 手术患者血浆、组织和手术部位组织中治疗性抗生素浓度的研究 2)设计治疗用β-内酰胺类抗生素的精确剂量图。 影响患者抗菌药物敏感性分布的定量组织PK-PD建模和模拟 人口统计和形态类型，以及在阑尾切除术中达到最佳组织暴露的时间；以及 3)试行和评估精确混合抗生素治疗和预防的有效性 用于阑尾切除术，为未来大规模传播做准备，由手术质量协作组进行。

Acute appendicitis is the most common abdominal surgical emergency in the world, with a lifetime risk of 8.6% in males and 6.9% in females. In the U.S., acute appendicitis affects > 280,000 individuals and contributes to 1 million patient days of admission each year. Surgical site infection (SSI) rates following appendectomy for uncomplicated, non-perforated appendicitis remain unacceptably high. A recent review reported pelvic abscess rates of 9.4% following appendectomy. The highest risks for microbial contamination of the peritoneum occur when the appendix is transected. Regardless of surgical technique, the retained appendiceal stump ALWAYS exposes appendiceal mucosa and luminal bacteria to the normally sterile peritoneal cavity. It is thus critical that optimal antibiotic tissue exposure occurs during this operative risk window. Antibiotic intervention for acute appendicitis is complex. Therapeutic antibiotics are initiated empirically in the emergency department, often hours before the appendectomy (usually a 4-18 hour wait). Thus, at the time of surgery, there are already therapeutic antibiotics on board, and the role of prophylactic antibiotics is unclear. To date, there has been no consensus on the blended use of therapeutic and prophylactic antibiotics for acute surgeries, and in many cases, prophylaxis is not administered because therapeutic antibiotics have already been administered. Unfortunately, in these instances antibiotic tissue levels are likely below the minimum inhibitory concentration at the time of appendiceal transection due to the short half-life and lack of protocoled dose timing relative to surgical incision. Consequently, the appendix, a known microbiome reservoir for the colon, has its lumen open to the peritoneum during appendectomy, guaranteeing some level of tissue and peritoneal microbial contamination during the surgery, increasing risk for SSI and abscess formation. A more personalized method of dosing antibiotics in patients with acute appendicitis could reduce SSI risk, limit unnecessary antibiotic use, reduce overdosing risks, and curb the development of antibiotic resistance. We hypothesize that personalized antibiotic dosing based on time to surgical appendectomy can optimize tissue antibiotic exposure at the surgical site, avoid use of unnecessary antibiotics (selective antibiotic resistance pressure), and reduce toxicity. Our Specific Aims are therefore to 1) characterize the plasma, tissue and surgical site tissue concentration of therapeutic antibiotics in patients undergoing appendectomy; 2) design a precision dosing nomogram for therapeutic beta-lactam antibiotics using quantitative tissue PK-PD modeling and simulation that factors antimicrobial susceptibility distributions, patient demographics and morphotypes as well as timing to achieve optimal tissue exposure at appendectomy; and 3) pilot and evaluate the effectiveness of a precision blended antibiotic treatment and prophylaxis nomogram for appendectomy in preparation for future large-scale dissemination by surgical quality collaboratives.